Benzothiophene aminoketones and aminoalcohols

ABSTRACT

X(-R1)(-R2)(-R3)-R4   THEIR SALTS AND QUATERNARY AMMONIUM COMPOUNDS, AS WELL AS THEIR OPTICALLY ACTIVE ISOMERS OR DIASTEREOMERS WHEREIN R1 TO R4 REPRESENT HYDROGEN, HALOGEN, LOWER ALKYL, ARALKYL, PHENYL, HYDROXYL, LOWER ALKOXY, NITRO OR LOWER CARBOALKOXY, R5 AND R6 ARE HYDROGEN OR METHYL, R7 AND R8 ARE HYDROGEN, HALOGEN OR LOWER ALKOXY, X IS A HETEROCYCLIC RING SYSTEM, MONO- OR CONDENSED BICYCLIC, WITH 1-4 HETERO ATOMS, IN WHICH THE INDIVIDUAL RINGS HAVE 5 TO 6 MEMBERS AND CAN ALSO CONTAIN 1 OR MORE CARBONYL GROUPS, Y IS -CO- OR -CH(OH)-. THESE COMPOUNDS HAVE PHARMACOLOGICAL ACTIVITY IN THAT THEY INCREASE THE CORONARY BLOOD FLOW BY SIMULTANEOUSLY CAUSING DILATION OF THE CORONARIES AND AN INCREASE IN CONTRACTION STRENGTH.   (R7,R8-PHENYL)-CH(-OH)-CH(-R6)-NH-CH2-CH(-R5)-Y- COMPOUNDS OF THE FORMULA

United States Patent 3,658,845 BENZOTHIOPHENE AMINOKETONES ANDAMINOALCOHOLS Klaus Posselt, Bergen-Enkheim, and Kurt Thiele, Frankfurtam Main, Germany, assignors to Deutsche Goldund Silber-Scheideanstaltvormals Roessler, Frankfurt am Main, Germany No Drawing. Originalapplication Dec. 26, 1967, Ser. No. 693,138, now Patent No. 3,514,465,dated May 26, 1970. Divided and this application Mar. 10, 1970, Ser. No.18,300 Claims priority, application Germany, Dec. 30, 1966, D 51,910,D51,911 Int. Cl. C0711 63/22 U.S. Cl. 260330.5 3 Claims ABSTRACT OF THEDISCLOSURE Compounds of the formula 1 a I R7 x-aq- CH-CH -NlI-CH-CH(OH)-38 n t 1. I

their salts and quaternary ammonium compounds, as well as theiroptically active isomers or diastereomers wherein R to R representhydrogen, halogen, lower alkyl, aralkyl, phenyl, hydroxyl, lower alkoxy,nitro or lower carboalk oxy, R and R are hydrogen or methyl, R and R arehydrogen, halogen or lower alkoxy, X is a heterocyclic ring system,monoor condensed bicyclic, with 1-4 hetero atoms, in which theindividual rings have 5 to 6 members and can also contain 1 or morecarbonyl groups, Y is -CO or -CH(OH). These compounds havepharmacological activity in that they increase the coronary blood flowby simultaneously causing dilation of the coronaries and an increase incontraction strength.

This application is a division of application Serial No. 693,138, filedDec. 26, 1967, and now U.S. Pat. No. 3,514,- 465 issued May 26, 1970.

DETAILED DESCRIPTION OF THE INVENTION INCLUDING PREFERRED EMBODIMENTSThe following heterocyclic ring systems, for example, come intoconsideration for the compounds according to the invention: furane,thiophene, pyrrole, pyrazole, thiazole, pyridine, pyrimidine, triazine,pyrazolone, benzofurane, benzothiophene, indole, quinoline,isoquinoline, benzodioxol, benzodioxane, decahydroisoquinoline,benzothiazole and benzimidazole.

The compounds according to the invention of the above Formula I can beproduced in a known manner by (a) reacting a compound of the formula\}IC-C O-C H2 RB/IH la n with a compound of the formula R1 HzN-OH(OH) iR8 III in the presence of formaldehyde or a formaldehyde source and asolvent.

(b) Reacting a compound of the formula or the corresponding Mannich baseof the formula 3,658,845 Patented Apr. 25, 1972 ice with a compound ofthe formula in which W and V are dilferent and are either halogen or NHin the presence of a basic substance and, if desired, in the event Y isCO, reducing such group to a CH(OH) group and, if desired, convertingthe bases produced into their pharmacologically acceptable acid additionsalts or quaternary ammonium salts.

The process according to method (a) is carried out in the usual mannerat a temperature between 20 and 150 C. Alcohols, dioxane, glacial aceticacid and the like come into consideration as solvents.

The process according to method (b) in general when using an unsaturatedketone of Formula IV can be carricd out at temperatures between 20 andC. in an inert solvent, such as, ether, acetone, dioxane or chloroform,whereas when the corresponding Mannich base is used, which during thereaction is transformed into an intermediate of Formula IV, the reactiontemperature used is normally higher, preferably, between 80 and C., andsolvents such as water, alcohol/Water, or a two phase system such asbenzene/water toluene/water come into consideration.

The process according to method (0) is usually carried out at elevatedtemperatures in a solvent such as alcohols, ether, dimethyl formamideand the like.

The compounds produced which contain optically active carbon atoms andwhich as a rule are produced as racemates can be resolved into theiroptically active isomers in the usual manner, for example, with the aidof an optically active acid. It, however, is also possible to employoptically active compounds or diastereomers as the starting materialswhereby the end product in the corresponding pure optically active formor diastereomeric configuration is obtained.

The free bases can be converted into their salts with the usualpharmacologically acceptable acids such as HCl, HBr, H 50 acetic acid,citric acid, succinic acid, maleic acid, fumaric acid, lactic acid,p-toluene sulfonic acid and the like. Those compounds containing basictertiary nitrogen atoms can be converted to their quaternary salts withthe usual pharmaoologically acceptable quaternizing agents such as thelower alkyl halides. The free bases can be removed from the salts, forexample, by treatment with aqueous NaOH and other salts can be preparedfrom such free bases.

As already indicated, the compounds according to the invention have apharmacological activity in that they increase the coronary blood flowby causing dilation of the coronaries, as well as an increase incontraction strength of the heart.

When tested on the isolated guinea pig heart according to Langendorif(Pfliigers Arch. 61, 291, 1895) it was found that the compoundsaccording to the invention were active in doses between 10-500,ug./heart (pg.='y

microgram) in dilating the coronaries while simultaneously increasingthe contraction strength.

The indications for the compounds according to the invention are:

Coronary insufl'iciency Angina pectoris Myocardial infarct Myocardialinsufiiciency Circulatory disturbances of various geneses Disturbancesof the peripheral and cerebral blood flow Migraines Arteriosclerosis Thenovel compounds can be used, if desired, also in combination with othermedicaments in the form of pharmaceutical compositions suited forenteral, parenteral, oral or per lingual application.

The acute toxicity of the compounds according to the invention whentested on mice by the method of Miller and Tainter (Proc. Soc. Exper.Biol. a Med. 57, 261, 1944) expressed as the LD' 50 is between 100mg./kg. and 5000 mg./kg. oral.

The individual doses for human beings, depending on form ofadministration are between 0.5 and 100 mg., one or more times a day.

The following examples will serve to illustrate the compounds accordingto the invention. For sake of simplicity the symbol Z is used in thestructural formulae and nomenclature of a number of the examples torepresent, respectively 2- 3-phenyl-3 -hydroxy-propyl- (2) -amino]-ethyl EXAMPLE 1 l-{2-[3-phenyl-3-hydroxy-propyl (2) amino-ethyl}-thienyl-*(2)-ketone, that is, 1-{Z}-thienyl-(2)-ketone Method (at) 12.6g. (0.1 mol) of Z-acetyl-thiophene, 18.7 g. (0.1 mol) ofl-norephedrine-HCl and 4 g. (0.13 mol) of paraformaldehyde weredissolved in 20 ml. of isopropanol and after addition of 0.2 mol ofconcentrated I-ICl boiled under reflux for 2 hours. Thereafter 100 ml.of acetone were added to the still warm solution. The hydrochloridewhich crystallized out upon cooling was purified by recrystallizationfrom ethanol. Its melting point was l91-192 C. and the yield 17 g.

Method (b) 1.5 g. (0.01 mol of l-norephedrine were dissolved in 50 ml.of ether and 2.7 g. (0.02 mol) of thienyl vinyl ketone dissolved in ml.of ether added thereto. After '-/2 hour 2 g. of the base separated outwhich after recrystallization from ethanol had a melting point of 118-120 C. The hydrochloride produced therefrom had a melting point of191l92 C.

Method (c) 5.2 g. (0.03 mol) of Z-[B-chloropropionyl]-thiophene weredissolved in dimethyl formamide and united with a solution of 4.5 g.(0.03 mol) of l-norephedrine and 4 g. (0.03 mol) of triethylamine in 25ml. of dimethyl formamide. After 1 hour the triethylamine HCl which wasformed was filtered ofi and the filtrate acidified with isopropanolicHCl. Subsequently, the HCl salt was precipitated from the solution byaddition of ether and recrystallized from ethanol. Its melting point was191-192" C. and the yield was 7 g.

4 EXAMPLE 2 1-{Z}-phenyl- (2) -ketone EXAMPLE 3 1- {Z}-[4-methyl-thiazolyl- 2) -ket0ne CH3 i loo-z 7 g. (0.05 mol) of4-methyl-Z-acetyl-thiazole, 9.4 g. (0.05 mol) of l-norephedrine-HCI, 2g. (0.067 mol) of paraformaldehyde and 5 drops of isopropanolic HCl in20 ml. of isopropanol were reacted and processed as in Example 2. TheHCl salt was recrystallized from methanol. Its melting point was l97199C. and the yield 7g.

EXAMPLE 4 l-{Z}-antipyryl-(4) -ketone 11.5 g. of 4-aceytl-antipyrin(0.05 mol), 9.5 g. of norephedrine-HCI (0.05 mol) and 2 g. ofparaformaldehyde (0.067 mol) were introduced into 20 ml. of isopropanoland 5 drops of isopropanolic HCl added thereto and the mixture boiledfor a total of 5 hours during which after 3 hours an additional 1 g. ofparaformaldehyde was added. Thereafter the solvent was distilled otf andthe residue treated with aqueous soda. The oily Mannich base producedwas crystallized with the aid of ether. It formed the dihydrochloridewith 2 mol of HCl which was recrystallized from ethanol. Its meltingpoint was 206-208 C. and the yield was 9 g.

EXAMPLE 5 1-{Z}-pyridyl-( 3 -ketone COZ 40 g. (0.33 mol) of3-acetyl-pyridine, 18.7 g. (0.1 mol) of l-norephedrine-HCI and 3 g. (0.1mol) of paraforrnaldehyde were boiled under reflux in 15 ml. ofisopropanol for a total of 3 hours. An additional 1 g. ofparaformaldehyde was added after 1 hour. Thereafter the reaction mixturewas diluted with acetone and the precipitated HCl salt wasrecrystallized from methanol/ ethanol (1:2). Its melting point was187l89 C. and the yield 7 g.

EXAMPLE 6 1-{Z}- 2,4-dimethyl-thiazolyl- (5) ]-ketone 25 g. (0.16 mol)of 2,4-dimethyl-S-acetyl-thiazole, 30 g. (0.16 mol) ofl-norephedrine-HCI and 5 g. (0.16 mol) of paraformaldehyde wereintroduced into 50 ml. of isopropanol and 15 drops of isopropanolic HCladded thereto. The mixture was boiled on a water bath for a total of 1hour. An additional 1.5 g. of paraformaldehyde was added after /2 hour.The reaction solution was diluted with 100 ml. of acetone while stillwarm. The HCl salt which precipitated out was recrystallized from 80%ethanol. Its melting point was 208-210" C. and the yield 6.6 g.

EXAMPLE 7 1-{Z}- [4-methyl-2-hydroxy-thiazolyl- (5 ]-ketone W noi C02 5g. (0.035 mol) of 4-methyl-2-hydroxy-5-acetyl-thiazole, 6.6 g. (0.035mol) of l-norephedrine-HCl and 1.5 g. (0.05 mol) of paraformaldehydewere boiled under reflux for 2 hours in 20 ml. of glacial acetic acid.The HCl salt which crystallized out on cooling was recrystallized frommethanol/ethanol (1:1). Its melting point was 209- 210" C. and the yield4.5 g.

EXAMPLE 8 1-{Z}-cumaronyl-ketone 1-3-'3-[3-phenyl-3-hydroxy-propyl-(2)-amino] propionyl}-thionaphthene 17.6g. (0.1 mol) of 3-acetyl-thionaphthene, 18.7 g. (0.1 mol) ofl-norcphedrine-HCI and 4.5 g. (0.15 mol) of paraformaldehyde were boiledunder reflux for 2 hours in 50 ml. of isopropanol. The solution was thendiluted with 100 ml. of acetone while still warm. Upon cooling the HClsalt precipitated out. It was recrystallized from methanol. Its meltingpoint was 220221 C. and the yield 18.5 g.

EXAMPLE 10 1-3-{3- [3phenyl-3-hydroxy-propyl-(2)-amino]- propionyl}-l-rnethyl-indole 25 g. (0.13 mol) of l-methyl-3-acetyl-indole, 24.3 g.(0.13 mol) of l-norephedrine-HCl and 5 g. (0.17 mol) of paraformaldehydewere dissolved in 100 ml. of isopropanol and boiled under reflux for atotal of 6 hours. After the second and fourth hours an additional 2.5 g.of paraforrnaldehyde were added. Thereafter the solvent was distilledoil and the residue dissolved in warm acetone. The HCl salt whichcrystallized out on cooling was recrystallized from ethanol. Its meltingpoint was 194195 C. and the yield 22 g.

EXAMPLE 11 1-5-{3-[3-phenyl-3-hydroxy-propyl-(2)-amino]-propionyl}-bcnzodioxol-( 1,3

8 g. (0.048 mol) of 5-acetyl-benzodioxol-( 1,3), 9.1 g. (0.048 mol) ofl-norephedrine-HCI and 2.9 g. (0.097 mol) of paraformaldehyde wereboiled on a water bath for 2 hours in 30 ml. of isopropanol afteraddition of 5 drops of isopropanolic HCl. After addition of ml. ofacetone to the warm reaction solution, the HCl salt precipitated out. Itwas recrystallized from ethanol. Its melting point was 195197 C. and theyield 9 g.

EXAMPLE 12 l-4 {3- [3 -phenyl-3 -hyd'roxy-propyl- (2 -amino]-propiomyl}-1,3-dimethyl and -1,5-dimethyl pyrazole (mixture) 26 g.(0.19 mol) of the isomeric mixture of 1,3- and 1,5dimethyl-4-acetyl-pyrazole formed during the synthesis, 37.4 g. (0.2mol) of l-norephedrine-I-ICI and 9 g. (0.3 mol) of paraformaldehyde wereboiled under reflux under an atmosphere of nitrogen in ml. ofisopropanol for 3 hours. Upon cooling the HCl salt crystallized. It wasrecrystallized from isopropanol and then twice from ethanol. Its meltingpoint was 196 C. and the yield 11 g.

EXAMPLE 13 10 g. (0.058 mol) of 3-acetyl quinoline, 11.2 g. (0.058 mol)of l-norephedrine-I-lCl and 1.6 g. (0.058 mol) of paraformaldehyde wereboiled under reflux on a water bath in 75 ml. of isopropanol for 2.5hours. An additional 0.8 g. (0.026 mol) of paraformaldehyde was addedafter 1 hours boiling. Upon addition of 150 ml. of acetone the HCl saltprecipitated out. It was recrystallized from 80% methanol. Its meltingpoint was 205-206 C. and the yield 5 g.

EXAMPLE l4 1-{Z}-isoquinolyl-(4)-ketone CO-Z 5 g. (0.024 mol) of4-acetyl isoquinoline-HCI, 4.6 g. (0.024 mol) of l-norephedrine-HCI and0.7 g. (0.024 mol) of paraformaldehyde were boiled on a water bath for2.5 hours in 50 ml. of a 1:1 mixture of ethanolisopropanol and anadditional 0.4 g. (0.012 mol) of paraformaldehyde was added after 1hours boiling. Upon cooling, the dihydrochloride salt precipitated out.It was recrystallized from ethanol. Its melting point was 208 C. and theyield 3 g.

7 EXAMPLE 15 1-{Z}- l,2,4-trimethyl-S-carbethoxypyrrolyl- 3 ]-ketoneEXAMPLE 16 1 -6{3- [3 -phenyl-3-hydroXy-propy1- (2) -amino] propionyl}-benzodioxane-( 1,4)

11.7 g. (0.066 mol) of 6-acetyl-1,4-benzodioxane, 12.5 g. (0.066 mol) ofl-uorephedrine-HCI and 2 g. (0.067 mol) of paraformaldehyde were boiledon a water bath in 33 ml. of isopropanol for 2 hours. An additional 2 g.(0.067 mol) of paraformaldehyde were added after 1 hour's boiling. Thesolvent was distilled off and the residue treated with acetone. The HCIsalt which precipitated out was recrystallized from ethanol. Its meltingpoint was 201' C. and the yield 7.5 g.

EXAMPLE 17 1-2{3-[3-phenyl-3-hydroxy-propyl-(2)-amino]-propionyl}-benzodioxane-( 1,4)

]-o o-z o 11 g. (0.061 mol) of 2-acetyl-1,4-benzodioxane, 11.6 g. (0.062mol) of l-norephcdrine-HCI and 1.85 g. (0.062 mol) of paraformaldehydewere reacted in 30 ml. of isopropanol and processed as in Example 16.The melting point of the HCl salt was 178 C. and the yield 8 g.

EXAMPLE 18 1-{Z}-[Z-benzyl-10-hydroxy-decahydroisoquinolyl- (4) -ketoneiI-CH -Q -11 g. (0.0339 mol) of2-benzy1-4-acetyl-l0-hydroxydecahydroisoquinoline-HCI, 6.5 g. (0.035mol) of 1- norephedrine-HCl and 1.4 g. (0.047 mol) of paraformaldehydewere boiled on a water bath for 2 hours in 35 ml. of isopropanol. Anadditional 1.4 g. of paraformaldehyde were added after 1 hours boiling.The solvent was then distilled off and acetone and ethyl acetate addedto the residue. The dihydrochloride produced was recrystallized fromethanol. Its melting point was 182-183 C. and the yield 7 g.

EXAMPLE 19 11.6 g. (0.075 mol) of Z-acetyl-S-nitro-furane, 14 g. (0.075mol) of 1-norephedrine-HC1 and 3 g. (0.1 mol) of paraformaldehyde in 50ml. of isopropauol were heated on a water bath for 3 hours. The HCl saltwhich precipitated out upon cooling was recrystalized from ethanol. Itsmelting point was 210 C. and the yield 3 g.

EXAMPLE 20 1-4-{3-[3-phenyl-3-hydroxy-propy1-(2)-amino]-propionyl}-1,3,5-trimethyl pyrazole CH3 C O Z N CH3 27 g. (0.178 mol) of1,3,5-trimethyl-4-acetylpyrazole, 33 g. (0.177 mol) ofl-norephedrine-HCI and 10.8 g. (0.36 mol) of paraformaldehyde in 150 ml.of isopropanol were heated for 2 hours on a water bath. Thereafter thesolvent was distilled oif and ml. acetone were added to the residue. TheHCl salt whcih precipitated was recrystallized from isopropanol. Itsmelting point was 191 C. and the yield was 14.5 g.

EXAMPLE 21 l-4-{3- 3-phenyl-S-hydroxy-propyl- (2) -amino]-propionyl}-l-benzyl- 3,5 dimethyl-pyrazole 13.5 g. (0.0624 mol) of3,5-dimethyl-1-benzyl-4-acetylpyrazole, 11.1 g. (0.0593 mol) ofl-norephedrine-HCI and 3.6 g. (0.12 mol) of paraformaldehyde were heatedon a water bath in 200 ml. of isopropanol for 2 hours. The HCl saltprecipitated out from the reaction solution after addition of 100 ml. ofacetone and it was recrystallized from ethanol. Its melting point was200 C. and the yield 11 g.

1 EXAMPLE 22 d,l-{2- [3- (3-fluoro-4-methoXy-phenyl -3-hydroxypropyl- (2-amino] -ethyl}-thienyl- (2) -ketone 28 g. (0.119 mol) ofd,l-3-(3-fluoro-4-methoxyphenyl)- 3-hydroXy-propy1-(2)-amine-HC1, 15 g.(0.119 mol) of 2- acetyl-thiophene and 7.2 g. (0.24 mol) ofparaformaldehyde were reacted in 200ml. of isopropanol and processed asin Example 21. The HCl salt was recrystallized from ethanol. Its meltingpoint was 208 C. and the yield was 10 g.

EXAMPLE 23 1-{ l- 3-phenyl-3-hydroXy-propyl- 2) -amino]- propyl- 2)}-thienyl- (2) -ketone 43 g. (0.307 mol) of 2-propionyl-thiophene, 57.7g. (0.308 mol) of l-norephedrine-HCI and 18.4 g. (0.614 mol) ofparaformaldehyde were heated on a water bath in 50 ml. of isopropanolfor 1 hour. 100 ml. of acetone were added to the reaction solution andthe HCl salt which precipitated out recrystallized from ethanol. Itsmelting point was 208 C. and the yield was 16.5 g.

9 EXAMPLE 24 1-{Z}-5-chloro-thieny1- (2) -ketone 30 g. (0.187 mol) of2-acetyl-5-chloro-thiophene, 35 g. (0.187 mol) of 1-norephedrine-HCl and5.6 g. (0.187 mol) of paraformaldehyde were heated in 50 ml. ofisopropanol and processed as in Example 21. The HCl salt wasrecrystallized from ethanol. Its melting point was 198 C. and the yieldwas 16 g.

EXAMPLE 25 d,l-{2- 2- (2-chl0ro-phenyl -2-hydroxy-ethylamino]ethy1}-thienyl- (2) -ketone 12.6 g. (0.1 mol) of 2-acetyl-thiophene,20.8 g. (0.1 mol) of d,1- 2 (2 chloro-phenyl)-2-hydroxy-ethylamine HCland 4.5 g. (0.15 mol) of parafor'maldehyde were heated on a water bathfor 2 hours in 100 ml. of isopropanol. Thereafter the solvent wasdistilled off and the residue caused to crystallized by addition ofethyl acetate. The HCl salt produced was recrystallized from ethanol.Its melting point was 158160 C. and the yield was 4 g.

EXAMPLE 26 [3 -phenyl-3-hydroxy-propyl- 2) ]-{3- [4-phenylthiazolyl- (2)]-3-hydroxy-propyl-( 1 }-amine i lCIEKOIED-Z 6 g. (0.015 mol) ofl-{Z}[4-phenyl-thiazo1yl-(2)]- ketone-HCl were suspended in 60 ml. ofmethanol and reduced by the addition of 0.6 g. (0.016 mol) of sodiumborohydride. After 1 hour the solvent was distilled off and the residuedissolved in acetone. Fumaric acid was added to such solution toprecipitate out the fumarate salt. The base was again set free from thefumarate with aqueous NaOH. The resulting oily base was taken up inether and converted to the HCl salt with isopropanolic HCl and such saltrecrystallized from ethanol. Its melting point was 178-181 C. and theyield was 2.5 g.

EXAMPLE 27 [3-phenyl-3-hydroxy-propyl- (2) -{3- [thienyl- (23-hydroxy-propyl-( 1 }-amine 63 g. (0.2 mol) of1-{Z}-thienyl-(2)-ketone-HCl and 300 g. of aluminum isopropylate wereheated to 130 C. for 2 hours in 2 liters of isopropanol and the acetoneproduced during the reduction distilled oil over a column. After 7 hoursthe cooled solution was decomposed by addition of 100 g. of citric acidin 200 ml. of water and then rendered strongly alkaline with aqueousNaOH. The organic phase was dried over calcium oxide and the solventdistilled oil under vacuum. The amino alcohol product melted at 123-125C. after it was recrystallized 10 from 50% ethanol. Upon addition of anequimolor quantity of HCl an HCl salt was obtained which had a meltingpoint of 152-155 C. The yield was 13 g.

EXAMPLE 28 [3-phenyl-3-hydroxy-propyl- 2) ]-{3- [cumaronyl- (2)3-hydroxypropyl-( 1 }-amine 18 g. (0.05 mol) of1-{Z}-cumaronyl-ketone-HCl were suspended in 100 ml. of ethanol andreduced at room temperature with 2 g. of sodium borohydride dissolved in50 ml. of ethanol. After 1 hour, 50 ml. of concentrated HCl were addedand the NaCl produced filtered off. The solvent was then distilled 01funder vacuum and the residue recrystallized from isopropanol/ethylacetate (1:1). The 0 HCl salt produced melted at 210-215" C. withdecomposition. The yield was 11 g.

EXAMPLE 29 [3-phenyl-3-hydroxy-propyl- (2) 3-thionaphthenyl- (3)]-3-hydroxy-propyl-(1)}-amine I OH R7 flqrorrommro H-hH-Q 8 R5 R5 Rs thepharmacologically acceptable salts thereof and the pharmacologicallyacceptable quaternary ammonium salts thereof, wherein R is selected fromthe group consisting of hydrogen, hydroxyl, nitro and lower carboalkoxy,R and R are selected from. the group consisting of hydrogen and methyl,R and R are selected from the group consisting of hydrogen, halogen andlower alkoxy and Y is selected from the group consisting of CO- and--'CH(OH)- 2. A compound according to claim 1 which is 1-3[3-[3-phenyl-B-hydroxypropyl (2) amino]-propionyl]-thionaphthene.

3. A compound according to claim 1 which is [3-phenyl-3 -hydroxypropyl(2) [S-thionaphthenyl- (3 ]-3-hydroxypropyl- 1 ]-amine.

HENRY R. JILES, Primary Examiner C. M. SHURKO, Assistant Examiner

